FDA accepts NDA for Lilly/BI’s empagliflozin/linagliptin SGLT-2/DPP-4 inhibitor fixed dose combination – April 14, 2014

Executive Highlights

  • The US FDA has accepted the filing of a new drug application (NDA) for Lilly/BI’s empagliflozin/linagliptin fixed dose combination tablet.
  • This is the first SGLT-2 inhibitor/DPP-4 inhibitor combination product ever filed for regulatory review.

Lilly/BI announced that the US FDA has accepted the new drug application (NDA) for the empagliflozin/linagliptin fixed dose combination (FDC). This represents the first submission for an SGLT-2 inhibitor/DPP-4 inhibitor combination product for regulatory review, raising the possibility that empagliflozin/linagliptin could be the first such FDC to market. Should the FDC undergo a standard review cycle, Lilly/BI could expect to receive a decision around February 20151. However, as a reminder, FDA approval for empagliflozin monotherapy has been delayed due to an issue at BI’s manufacturing plant in Germany, and it is unknown how quickly that issue may be resolved. Since empa/lina is its own new molecular entity, its approval does not necessarily depend on the approval of empagliflozin, but since empa/lina and empagliflozin are produced at the same facility, we would presume that any issues affecting empa/lina production would also need to be resolved prior to approval.  Lilly management commented during the company’s 2014 financial guidance call that a European empagliflozin/linagliptin submission is expected in 2015 (read our report), a timeline that we would not expect to be adversely affected by the BI factory issue.

Excitement has been mounting for the SGLT-2 inhibitor/DPP-4 inhibitor FDC class, which combines two classes with attractive and complementary profiles. DPP-4 inhibitors, which increase levels of endogenous GLP-1, have modest A1c-lowering efficacy with minimal safety/tolerability issues and are weight neutral. SGLT-2 inhibitors, which lower blood glucose through urinary glucose excretion, operate through an insulin-independent mechanism. The combination of these two classes should yield an additive effect on glucose-lowering efficacy. Additionally, DPP-4 inhibition may help blunt the paradoxical rise in hepatic glucose production seen with SGLT-2 inhibitors, which (according to some data) eliminates half of the class’ glycemic effect (see our CODHy Latin America Report for more detail on this front). Beyond glycemia, SGLT-2 inhibitors have weight and blood pressure benefits, although they are associated with a slight increase in LDL cholesterol as well as genitourinary infections (which generally respond to treatment and only rarely lead to discontinuation of therapy). Both DPP-4 inhibitors and SGLT-2 inhibitors also have a low risk of hypoglycemia. The SGLT-2 inhibitor/DPP-4 FDC class should have one of the best benefit/risk profiles of any currently available once-daily oral treatment for type 2 diabetes (the other once-daily oral drug classes on the market being metformin, DPP-4 inhibitor monotherapy, SGLT-2 inhibitor monotherapy, TZDs, sulfonylureas, glinides, DPP-4 inhibitor/metformin FDCs, TZD/metformin FDCs, and one DPP-4 inhibitor/TZD combination [Takeda’s Oseni]).

  • Lilly/BI’s NDA filing follows completion of a phase 3 study of the empagliflozin/linagliptin FDC in treatment naïve patients and patients on background metformin therapy ( Identifier NCT01422876). This was a 52-week trial with primary endpoint of A1c change from baseline to 24 weeks (n=1,406). Lilly’s press release indicates that the results of this study will be presented later this year. According to, Lilly/BI are also recruiting for a study comparing empagliflozin/linagliptin to linagliptin alone (Lilly/BI’s Tradjenta) over 24 weeks ( Identifier: NCT01734785; estimated primary completion date of May 2015) and another study on linagliptin as add on to empagliflozin in people with background metformin therapy ( Identifier: NCT01778049; estimated primary completion date May 2015).
  • AZ also has an SGLT-2 inhibitor/DPP-4 inhibitor FDC in development (saxagliptin/dapagliflozin), which it expects to submit in 4Q14. Following AZ’s acquisition of BMS’ diabetes business, AZ CEO Mr. Pascal Soriot expressed particular enthusiasm about this candidate (see our AZ 4Q13 Report). Merck and Pfizer partnered up in early 2013 to develop Pfizer’s SGLT-2 inhibitor ertugliflozin (now phase 3), and should ertugliflozin ultimately succeed, the companies will pursue a Januvia/ertugliflozin FDC. J&J does not have an in-house DPP-4 inhibitor to pair with its SGLT-2 inhibitor (Invokana). Takeda and Novartis currently do not have in-house SGLT-2 inhibitors to pair with their DPP-4 inhibitors. We continue to believe Takeda and J&J would be natural partners on this front to make an SGLT-2 inhibitor/DPP-4 inhibitor FDC with Invokana and Takeda’s Nesina. Novartis is developing an early stage SGLT-1/SGLT-2 dual inhibitor in-house, so it may ultimately elect to develop a Galvus FDC with this agent. Lexicon’s LX4211 (another SGLT-1/SGLT-2 dual inhibitor) is another candidate that could possibly be combined with a DPP-4 inhibitor.   


-- by Jessica Dong, Manu Venkat, and Kelly Close

1Under PDUFA V, the FDA generally “accepts” the NDA about two months after the sponsor’s initial filing. A 10-month review period follows the “acceptance” of an NDA.